Department of Molecular Medicine and Surgery, Karolinska Institutet, von Eulers väg 4a, IV, SE-171 77, Stockholm, Sweden.
Endocrinology. 2011 Jun;152(6):2237-46. doi: 10.1210/en.2010-0040. Epub 2011 Apr 26.
Leptin regulates food intake and energy expenditure by activating the long form of the leptin receptor (LepRb). Leptin also regulates glucose homeostasis by improving whole-body insulin sensitivity, but the mechanism remains undefined. Leptin action is mediated by phosphorylation of several tyrosine residues on LepRb. LepRb-Tyr985 plays an important role in the attenuation of LepRb signaling. We determined the contribution of LepRb-Tyr985-mediated signals to leptin action on insulin sensitivity using LepRb-Tyr985 mutant mice (l/l mice). Glucose tolerance and whole-body insulin-mediated glucose utilization were determined in wild-type (+/+) and l/l mice. Glucose tolerance was unaltered between female +/+ and l/l mice but enhanced in the male l/l mice. Serum insulin concentration was decreased at baseline and 15 min after a glucose injection in female l/l vs. +/+ mice (P < 0.05) but unaltered in the male l/l mice. However, basal and insulin-stimulated glucose transport in isolated soleus and extensor digitorum longus muscle was similar between +/+ and l/l mice, indicating skeletal muscle insulin sensitivity in vitro was not enhanced. Moreover, euglycemic-hyperinsulinemic clamps reveal hepatic, rather than peripheral, insulin sensitivity is enhanced in female l/l mice, whereas male l/l mice display both improved hepatic and peripheral insulin sensitivity. In conclusion, signals emanating from leptin receptor Tyr985 control hepatic insulin sensitivity in both female and male l/l mice. Lack of LepRb-Tyr985 signaling enhances whole-body insulin sensitivity partly through increased insulin action on the suppression of hepatic glucose production.
瘦素通过激活长形式瘦素受体（LepRb）来调节食物摄入和能量消耗。瘦素还通过改善全身胰岛素敏感性来调节葡萄糖稳态，但具体机制尚不清楚。瘦素的作用是通过 LepRb 上几个酪氨酸残基的磷酸化来介导的。LepRb-Tyr985 在衰减 LepRb 信号转导中起着重要作用。我们使用 LepRb-Tyr985 突变小鼠（l/l 小鼠）确定了 LepRb-Tyr985 介导的信号对瘦素作用于胰岛素敏感性的贡献。在野生型（+/+）和 l/l 小鼠中测定葡萄糖耐量和全身胰岛素介导的葡萄糖利用。雌性 +/+ 和 l/l 小鼠之间的葡萄糖耐量没有改变，但雄性 l/l 小鼠的葡萄糖耐量增强。与雌性 +/+ 小鼠相比，雌性 l/l 小鼠的基础血清胰岛素浓度和葡萄糖注射后 15 分钟时降低（P <0.05），但雄性 l/l 小鼠的血清胰岛素浓度没有改变。然而，+/+ 和 l/l 小鼠的分离比目鱼肌和伸趾长肌中的基础和胰岛素刺激的葡萄糖转运相似，表明体外骨骼肌胰岛素敏感性没有增强。此外，在正常血糖高胰岛素钳夹试验中发现，雌性 l/l 小鼠的肝胰岛素敏感性增强，而非外周胰岛素敏感性增强，而雄性 l/l 小鼠则显示肝和外周胰岛素敏感性均增强。总之，来自瘦素受体 Tyr985 的信号控制雌性和雄性 l/l 小鼠的肝胰岛素敏感性。缺乏 LepRb-Tyr985 信号转导通过增加胰岛素对抑制肝葡萄糖生成的作用，部分增强了全身胰岛素敏感性。
